Project Summary/Abstract Fragile X Syndrome (FXS) is the leading cause of intellectual disability and autism as a result of mutations to a single gene. Approximately 1 in 4,000 males and 1 in 8,000 females are diagnosed with FXS. The disorder causes a range of developmental problems including learning disabilities and cognitive impairment. Hyperactive behavior and anxiety are common in children with FXS and they may be diagnosed with attention deficit disorder. About one-third of afflicted individuals have features of autism spectrum disorders while seizures occur in 15 percent of males and 5 percent of females. Loss of expression of the fragile X mental retardation protein (FMRP) is the root cause of FXS. FMRP is an important RNA binding protein that regulates translation of a wide variety of proteins in neuronal dendrites and synapses, the specialized structures that form connections between neurons. One widely reported feature of FXS is the increased tendency for neurons to fire electrical impulses. Neurons are complex structures, and while the axon fires electrical signals to other neurons, it is the large tree like structure formed by the dendrites that receives thousands of synaptic inputs and is responsible for bringing the neuron to the firing threshold. Surprisingly, very little is known about how FMRP regulates local translation of important proteins in synapses and dendrites that regulate excitability. In aim 1, we will determine how FMRP regulates dendritic protein synthesis and excitability using new techniques to visualize newly synthesized proteins and to excite dendrites and spines locally. Dendrite excitation is a result of electrical gradients brought about by synaptic transmission and this is critically dependent upon ion channels. In aim 2, we will determine the role of FMRP in regulating translation of two particular ion channels that we have identified as both important for dendritic excitability and are regulated by FMRP function. At the conclusion of these studies we will have expanded our knowledge of FMRP function in local translation at synapses of hippocampal neurons. In particular, we will visualize and measure FMRP translational regulation of two ion channels that are critical determinants of neuronal excitability. The results of these studies may lead to identification of new drug targets in the treatment of Fragile X Syndrome.